Project 3 "Genetic Analysis of SMN Pathways in C. elegans" Summary Spinal Muscular Atrophy (SMA) is one of the most common inherited genefic disordersV The corresponding SMN (Spinal Motor Neuron) protein is essential in all cells as SMN is a critical component of the Gemin complex that assembles protein/RNA complexes critical for mRNA translation and processing^. However, recent studies suggest that the SMN protein may also act in stress granules and axonal mRNA transport^. We do not understand why decreased function of SMN causes selective neuromuscular degeneration nor is there consensus on which molecular pathways are critical for SMA pathology. The C. e/egans genome contains only one SMN gene {smn-1 or Cesmn-1) and loss of Cesmn-1 function causes defective development, progressive behavioral defects, and premature death. C. elegans and Drosophila are ideal for the identification and validation of molecular pathways relevant to biological processes;the genefic dissecfion of apoptosis is an excellent example of the power of harnessing invertebrate models. In the studies proposed here, we will identify conserved modifier genes and cellular pathways that are critical for SMN loss of function neuromuscular defects. We utilize C. elegans assays to identify and characterize genes that act as modifiers of SMN loss of function defects.